1. Field of the Invention
The present invention relates to drug delivery. More particularly, the present invention relates to methods and apparatus for delivering agents that cause vasoconstriction to mucosal and other tissue surfaces in the presence of capnic gases, particularly for the treatment of migraine headaches.
Drug delivery to mucosal surfaces, such as the mucosa of the nose, is well known. While in some cases drugs delivered to the nose and other mucosal surfaces are intended to have local effect, more often such transmucosal drug delivery is intended for systemic administration. In either case, penetration of the drug into or through the mucosa is limited by the ability of the particular drug to pass into or through the mucosal cell structure. Such resistance from the mucosal cell structure can result in slowing of the delivery, the need to use higher dosages of the drug, or in the case of larger molecules, the inability to deliver via a nasal or other mucosal route.
Migraine headaches are a form of severe headache that tends to recur in susceptible patients. Migraine headaches may be accompanied by associated symptoms, such as nausea, vomiting, hypersensitivity to light, sound and odor. Patients suffering from migraines often must remain immobile since even small movements can exacerbate the pain. In “classic” migraine etiology, the patient often experiences an aura some ten to thirty minutes before the onset of the migraine. The aura may include a perception of flashing lights, zigzag lines, or in some instances may even cause temporary vision impairment. So-called “common” migraines are not preceded by such an aura. Both types of migraines may occur as often as several times a week or as rarely as once every few years.
Migraines are most often treated using drugs that cause vasoconstriction. For years, ergotamines was the primary drug available for treating severe migraine pain. More recently, triptan drugs have become available for treating all forms of migraine.
While drug therapy using triptans and ergotamines are often effective, the drugs can require one to two hours to reach effective plasma concentrations. Even so-called quick acting forms, such as quick-melt tablets, intra-nasal sprays, injectable forms of the drugs, and topical forms of the drug, still have significant lag times before they become effective. Moreover, not all individuals benefit from triptans, ergotamines, or other drug therapies for migraines.
Very recently, the use of carbon dioxide and other capnic gases alone and in combination with other gases has been proposed for the treatment of migraine headaches and other conditions. The carbon dioxide is preferably delivered to nasal or other mucosa without inhalation. It is believed that the carbon dioxide may cause an acidosis which inhibits the release of calcitonin gene-related peptide (CGRP) which in turn reduces the pain and associated symptoms resulting from the migraine. It has also been found that the onset of relief is usually much more rapid than that achieved with triptans, ergotamines, and other systemic drug therapies.
Despite the promise of conventional drug therapies and the newer delivery of capnic gases, neither therapy is effective in all individuals and neither therapy is entirely effective in relieving all migraine pain and associated symptoms in all circumstances. It would thus be desirable to provide improved methods and systems for treating migraine headaches. In particular, it would be desirable to provide treatments which are more effective, more rapid, more long-lasting, and/or which have other benefits when compared to the administration of either known systemic drugs or capnic gases alone.
2. Description of Background Art
Inhalation devices, systems and methods for delivering carbon dioxide and other gases and aerosols to patients, with and without co-delivery of a drug are described in U.S. Pat. Nos. 3,776,227; 3,513,843; 3,974,830; 4,137,914; 4,554,916; 5,262,180; 5,485,827; 5,570,683, 6,581,539; and 6,652,479. While some methods and devices provide for co-delivery of a drug and carbon dioxide or other gases, the purpose is usually not potentiation. For example, carbon dioxide may be used as a safe propellant, as shown in Wetterlin, U.S. Pat. No. 4,137,914. See also copending application Ser. Nos. 09/614,389; 10/666,947; and 10/666,562, the full disclosures of which are incorporated herein by reference.
Additional background art may be found in the following references: Guyton A C, Hall J E. Textbook of Medical Physiology. Ninth Ed., W.B. Saunders Co., Philadelphia, 1996; Tang A, Rayner M, Nadel J. “Effect of CO2 on serotonin-induced contraction of isolated smooth muscle,” Clin Research 20:243, 1972; Qi S, Yang Z, He B. “An experimental study of reversed pulmonary hypertension with inhaled nitric oxide on smoke inhalation injury,” Chung Hua Wai Ko Tsa Chih 35(1):56-8, January 1997; Loh E, Lankford E B, Polidori D J, Doering-Lubit E B, Hanson C W, Acker M A. “Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy,” Ann Thorac Surg 67(5): 13 80-5, May 1999; Pagano D, Townend J N, Horton R, Smith C, Clutton-Brock T, Bonser R S. “A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation,” Eur J Cardiothorac Surg 10(12):1120-6, 1996; and Sterling G, et al. “Effect of CO2 and pH on bronchoconstriction caused by serotonin vs. acetylcholine,” J of Appl Physiology, vol. 22, 1972.